Modular gene networks as agents of evolutionary novelty

A while back, I told you all about this small piece of the biochemistry of the fly eye — the pathways that make the brown and red pigments that color the eye.

I left it with a question: if even my abbreviated summary revealed considerable complexity, how could this pathway evolve? Changing anything produces a failure or change in the result. Before I answer, let’s make the problem even harder, because I love a challenge (although actually, I’m cheating — it’s going to turn out that complexity is not a barrier, but an opportunity).

The pigment pathways above are far downstream: they operate in the differentiated compound eye of the fly. Long before that, there are a set of genes that have to be activated first to trigger formation of the head and eye in the larva. And this is that pathway:


Regulatory scheme on the top of the eye developmental pathway. Twin of eyeless (toy), eyeless (ey), and possibly eyegone (eyg), three Pax genes, are master control genes on the top of the hierarchy. Sine oculis (so), eyes absent (eya), dachshund (dac), and optix are second-order transcription factors regulated by the master control genes. Note that the pathway is not linear, but rather a network interconnected by feedback loops.

At the top of the hierarchy are two genes in Drosophila, eyeless (ey) and twin of eyeless (toy). Remember, genes are named for their mutant effect, so the normal function of eyeless is to initiate eye development. These genes switch on sine oculis and eyes absent (notice the effort to find synonyms to describe genes that cause missing eyes when broken) that activate each other and feed back on eyeless to generate a robust response. Another gene, dachshund (this one named for another part of its phenotype: it makes flies with very short legs) also feeds back on eyeless.

This circuit has multiple outputs: so, dac, optix and eyg. All of these have effects further downstream, in that catch-all category labeled “eye development” here. In that broad label lie multiple processes: the pigment pathways above, but also all kinds of elaborate interactions that recruit cells to specific photoreceptor functions, that organize supporting cells, like hair cells and lenses, and that induce the neural tissue of the retina and deeper parts of the nervous system. The genes ey and toy initiate a whole deep, branching network of genes that cascade together to build the many bits and pieces of the eye.

These two master control genes, eyeless and twin of eyeless, also have a synonym. To everyone’s surprise, versions of this circuit are found in all animals with eyes, and the common name for this universal regulator of eye formation is Pax6, and that’s what I’ll call it in the rest of this article.

And look at this! Isn’t it cool? All these eyes use this same Pax6 gene regulatory network to initiate development.


General scheme of eye evolution. The first step in eye evolution is the evolution of a light receptor molecule which in all metazoans is rhodopsin. In the most ancestral metazoa, the sponges, a single Pax gene, but no opsin gene has been found. In the cubozoan jellyfish Tripedalia, a unicellular photoreceptor has been described in the larva. The adult jellyfish has complex lens eyes that form under the control of PaxB, whereas the eyes of a hydrozoan jellyfish (Cladonema) are controlled by PaxA. We propose that from the unicellular photoreceptor cell, the prototypic eye postulated by Darwin originated by a first step of cellular differentiation into a photoreceptor cell and a pigment cell, controlled by Pax6 and MITF, respectively. From this prototype, all the more complex eye types arose monophyletically. As a mechanism, we propose intercalary evolution of progressively more genes such as lens genes into the eye developmental pathway (after Gehring and Seimiya 2010). Starting from the common prototype, the various eye types evolved by divergent, parallel, and convergent evolution, generating a magnificent biodiversity.

That’s the power of a gene regulatory network. Switch on just one of the key genes, and it recruits all the downstream genes and triggers a whole series of actions to assemble a complex structure. That strange grey object to the right is a developing Drosophila wing — the dark fringe is the line of bristles that surround the leading and trailing edges of the fully-formed wing — which has had the Pax6 gene inappropriately expressed in a few cells at the base. Just switching on that one gene has led to the construction of an eye with its red pigment right there, where flies should not have eyes.

The ability to build elaborate organs with a simple switch is a reflection of the modular nature of developmental programs. It also simplifies evolution; small, simple changes can lead to dramatic novelties. Zap, one mutation can lead to an abrupt saltational change.

Now wait a moment, you will say. Suddenly plopping an eye onto a wing sounds disastrous: it really is a kind of hopeful monster, emphasis on “monster”, and is almost always going to be grossly deleterious. This can’t be a viable pathway for evolutionary change, can it? And you’d be right. But what about portions of a pathway? Look back up at the eye development pathway, the second figure in this article. What if you just switched on optix, one of the second-order transcription factors? Then you’d just activate some of the tools of eye construction.

It’s been done. The hideous blob to the left is the nascent antenna of a fruit fly, and optix has been inappropriately switched on…and what do you get? It activates the pigment pathway (that biochemical sequence illustrated in the first image at the top of this page), and it creates a bright red spot on the antenna. This is non-trivial; it means the precursors and transporters are all at work, and all the enzymes in the xanthomattin and drosopterin pathways are doing their job. One switch, and you get a whole hierarchy of genes producing a complex output. This could be one way new traits appear, by redeploying genes from established pathways.

Saying they could isn’t the same as saying they did, of course. But here are a few examples that suggest that eye network genes have been redeployed to create morphological novelties. In Heliconius butterflies, for instance, the red spots on their wings can be traced back to embryonic patterns of expression of optix in the developing wings.


Heliconius butterflies express optix in wing epidermal cells that will produce red ommochrome pigments. A: Heliconius erato. B: Forewing and hindwing patterns from different races of H. erato (top: H. e. petiverana; bottom: H. e. erato). C: Pupal wings expressing optix mRNA in a pattern corresponding to the areas of red pigment in wings depicted in (B).

Even more dramatically, here’s an extinct biting midge preserved in amber, and look at that wing: what was I saying about switching on eye genes inappropriately in the wing would be deleterious? I was wrong. This is an insect with a compound eye growing in its wing.


A. The extinct biting midge, Eohelea petrunkevitchi, with a unique wing organ that resembles the surface of its compound eye. B: The dorsal surface of the wing organ. C: The midge’s compound eye. D: The ventral surface of the wing organ.

It’s extremely unlikely that that alar eye functioned as a visual organ: any photoreceptor signals coming from a platform flapping several times a second would be hopelessly confusing. Most likely what it was was a species-specific sexual signal, like the spots on many fly wings — this one is just more elaborately structured and expensive than most. Alternatively, one hypothesis for the formation of spots on insect wings is that they are intended to resemble eyes — large eyes, far apart, making the animal look much larger to predators — so Eohelea may have just been carrying the eyespot mimicry to an extreme. Either way, building these eyes is developmentally trivial.

It may also represent a transitional state: first the initiator of a genetic cascade is co-opted and expressed at a novel time or place, and then selection can hone it down over time, adding new control points that, for instance, suppress irrelevant ommatidium formation in the alar eye while allowing the functional pigment expression to continue.

One last example: this is the Cambrian worm, Microdictyon. Notice anything unusual?


Microdictyon sinicum, a Cambrian Lobopodian fossil from Chengjiang (China) with compound eye on every annulus (segment) above every leg. (A) Reconsruction (after Bergström and Hou). (B) Lateral view.

There’s a pair of eyes in the head, where you’d expect them…but all those other eyes along the sides are morphologically indistinguishable from the anteriormost pair. There is some argument about whether these structures actually are eyes, but they are definitely hexagonal arrays that closely resemble the hexagonally structured ommatidia of the compound eyes of insects. If they weren’t functional eyes, it seems likely that they are at least produced by the redeployment of the structural genes of the compound eye.

And if they were functional eyes, well, that is just freakin’ cool.

The bottom line, though, is that because complex developmental networks are functionally constrained — think of them as software modules that respond to molecular inputs and produce morphological outputs — their complexity is not a barrier to evolution at all, but instead provide opportunities for generating interesting evolutionary novelties.

Gehring WJ (2012) The animal body plan, the prototypic body segment, and eye evolution. Evolution & Development 14(1):34-36.

Monteiro A (2012) Gene regulatory networks reused to build novel traits. Bioessays 34:181-186.

(Also on Sb)

Now you, too, can be a cephalopedant

You remember all those dinosaur books you read as a kid, page after page listing species, with illustrations? (Wait, you don’t? What was wrong with you?) Well, now you’ve got the same thing for cephalopods, and it’s all free. You can download two volumes in pdf form of a massive catalog of species, all for yourself. Put ’em on your iPad, and then you can read it under the covers in bed. Hey, I just realized…this generation may be the last to do the ol’ “smuggling books and a flashlight into bed to read past your bedtime” thing — tablets make the whole procedure so much easier.

Here are the two volumes; each is about 20Mb.

Jereb, P.; Roper, C.F.E. (eds) Cephalopods of the world. An annotated and illustrated catalogue of cephalopod species known to date. Volume 1.
Chambered nautiluses and sepioids (Nautilidae, Sepiidae, Sepiolidae, Sepiadariidae, Idiosepiidae and Spirulidae).
FAO Species Catalogue for Fishery Purposes. No. 4, Vol. 1. Rome, FAO. 2005. 262p. 9 colour plates.

This is the first volume of the entirely rewritten, revised and updated version of the original FAO Catalogue of Cephalopods of the World (1984). The present Volume is a multiauthored compilation that reviews six families: Nautilidae, Sepiidae, Sepiolidae, Sepiadariidae, Idiosepiidae and Spirulidae, with 23 genera and the 201 species known to the date of the completion of the volume. It provides accounts for all families and genera, as well as illustrated keys to all taxa. Information under each species account includes: valid modern systematic name and original citation of the species (or subspecies); main synonyms; English, French and Spanish FAO names for the species; illustrations of dorsal and ventral aspect of the whole animal (as necessary) and other distinguishing illustrations; field characteristics; diagnostic features; geographic and vertical distribution, including GIS map; size; habitat; biology; interest to fishery; local names when available; a remarks section (as necessary) and literature. The volume is fully indexed and also includes sections on terminology and measurements, an extensive glossary, an introduction with an updated review of the existing biological knowledge on cephalopods (including fisheries information and catch data for recent years) and a dedicated bibliography.

Jereb, P.; Roper, C.F.E. (eds) Cephalopods of the world. An annotated and illustrated catalogue of cephalopod species known to date. Volume 2.
Myopsid and Oegopsid Squids.
FAO Species Catalogue for Fishery Purposes. No. 4, Vol. 2. Rome, FAO. 2010. 605p. 10 colour plates.

This is the second volume of the entirely rewritten, revised and updated version of the original FAO Catalogue of Cephalopods of the World (1984). The present Volume is a multiauthored compilation that reviews 28 families, i.e. (in alphabetical order), Ancistrocheiridae, Architeuthidae, Australiteuthidae, Bathyteuthidae, Batoteuthidae, Brachioteuthidae, Chiroteuthidae, Chtenopterygidae, Cranchiidae, Cycloteuthidae, Enoploteuthidae, Gonatidae, Histioteuthidae, Joubiniteuthidae, Lepidoteuthidae, Loliginidae, Lycoteuthidae, Magnapinnidae, Mastigoteuthidae, Neoteuthidae, Octopoteuthidae, Ommastrephidae, Onychoteuthidae, Pholidoteuthidae, Promachoteuthidae, Psychroteuthidae, Pyroteuthidae and Thysanoteuthidae, with 83 genera and the 295 species known and named to the date of the completion of the volume. It provides accounts for all families and genera, as well as illustrated keys. Information under species accounts includes: valid modern systematic name and original citation of the species (or subspecies); synonyms; English, French and Spanish FAO names for the species; illustrations of dorsal and ventral aspects of the whole animal (as necessary) and other distinguishing illustrations; field characteristics; diagnostic features; geographic and vertical distribution, including GIS map; size; habitat; biology; interest to fishery; local names when available; a remarks section (as necessary) and literature. The Volume is fully indexed and also includes sections on terminology and measurements, an extensive glossary, an introduction with an updated review of the existing biological knowledge on squids (including fisheries information and main catch data for recent years) and a dedicated bibliography. Due to the conspicuous amount of literature addressing many squid species, an appendix is included in the online version, where those references considered most pertinent to the species are listed, by family and species, in alphabetical order by author; key words, also, are reported.

There. Now everybody should be happy.

More juicy stuff for Minnesotans

Sorry, all you foreigners who don’t live in an awesome state like Minnesota, but I have to mention another cool local series of events. The Hennepin County Library is sponsoring DNA Day, with multiple opportunities to learn about genetics, genetic diseases, cancer genetics, and genetic family trees. I don’t know why it’s called DNA Day, though, because they have multiple events spread out between 19 April and 1 May at various libraries around Minneapolis. There is limited space, so registration is required (these events are free, though), and you’d better get in there fast.

WORST. INTERNET. ACCESS. EVER.

It’s a fantastic meeting here at #atheistcon, in a beautiful part of the world, with huge crowds (I have seen the theater, and I have seen it filled with people, and I am intimidated), and I can tell this convention is going to be a huge success. But I have to complain about one thing, and that is the internet access. It’s no fault of the organizers, but it’s a universal problem of big greedy hotels.

I can say from experience staying at way too many hotels that the South Wharf Hilton in Melbourne has provided the very worst experience in wifi ever. It’s abominable. Let me tell you what fun I’ve had.

The first day was OK; we actually briefly had free access. Everything was smooth, I was pleased, but of course it could not last, because then it stopped working altogether — we were told that they were going to fix it.

The next day, it was sort of working. My wife and I could both get on, I could access it via my iPad, but that’s also where my laptop started mysteriously crashing (a problem that has since vanished, since new wifi software started working).

Later that day, though, everything changed. We’d connect with wifi, and get a login screen for “DOCOMO Intertouch”. What, you might ask, is this? It’s what greedy hotels install to fuck up the internet and bring in some additional revenue. You log into this thing and then all your access is filtered through this new layer that exists solely to monitor your usage and cut you off at a specified time limit. And it sucks.

The cost is $9.95au for two hours, which is absurdly overpriced. Nothing is too absurd for these hotels, though, because when I tried to use their Business Center, the machines there charge $26au for two hours. No thanks.

So I composed some stuff offline, and bit the bullet and paid the $9.95 to get some stuff done. I started sucking in my email, managed some essential student business, then after about ten minutes went to do some of that blogging stuff, and this is what I got instead, a big stupid error message.

image will be posted when I have better access

I followed the instructions, quit and restarted, and fired it up again…no go. Same message. Infuriatingly, the lovely DOCOMO software does put up a little countdown clock to tell you that your time will expire in 1Hour(s):43Min(s): 14Sec(s), which you can watch count down to the time it will stop working for sure. Just the fact that they use that clumsy (s) tells me these programmers are lazy relics from the 1980s. Maybe the DOCOMO code is even written in COBOL.

I let it time out.

So today, fool that I am, I figured they’ve been working on fixing this problem, and I paid them $9.95 again. I got about 3 minutes before it died. I thought I’d be smart and try to post something first; I wasn’t quick enough. So that morning I got to watch the ever-so-useful timer count down again.

Oh, well.

I’ve run into this so often it’s become a kind of expectation for me. I get a cheap hotel, the room is fine, the internet access is routine and free; sometimes you have to enter a password, but that’s a function built into the router and it all works smoothly. Get put into a pricier, nicer, fancier hotel, and oh, no, they can’t possibly just provide access to all their customers — they have to gouge more money out of them. So they contract some company to build a wall, usually badly, that their residents have to pay to get through, and then they charge some ridiculous sum for limited access. And it almost always breaks, because the people running the hotel have no idea how to manage this clumsy chunk of code they’ve interposed between us and the internet. And we get really pissed off.

Because, you know, a hotel may have lovely amenities (like this one), but some of us see the world through the lens of the network, and all we see is incompetent IT people and money-grubbing asshole management, and that means the hotel looks utterly hideous to us.

The hotel staff did try to be helpful, and cancelled the charges, but none of them knew anything about the software, and the only way they could actually help me get on the internet was to connect me to DOCOMO. No thanks. They are the problem, not the solution.

Travelers, if you expect to get anything done on the internet, stay away from the South Wharf Hilton in Melbourne. All you’ll get is aggravation and frustration. Stay just about anywhere else — I’ve talked to a few people who got cheaper local accommodation, and they’re entirely content with their service.

Some good news: we do have free wifi in the convention center! Hooray for the organizers! I’ll try to post a few updates on the meetings throughout the Australian day (first up this morning: Peter Singer), but I also suspect that, realistically, once 3500-4000 people show up and fire up their smartphones all at once, it may get a little flaky. But at least I have one place where I can get through!

Why privacy matters

We missed out. This iPhone app, Girls Around Me, has been yanked from the Apple store. It was a geolocation based mapping application that created a google map of your current location, and then checked in with facebook to find all the women who had done any social networking in that area. Then it tracked through their data to post pictures of them on the map.

Isn’t that sweet? All you women were made public targets for a kind of weird hunting game. I presume you are all now logging into facebook and trying to sort through the arcane tangle of options to limit access.

In case you’re thinking this was an app designed for creepy stalkers, though, you’ve got it all wrong. It’s the opposite of stalking. The designer has said that the purpose of the app was to allow his bros to avoid the ugly girls.

Doesn’t that make you feel so much better now?